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The economic crisis in 2008 instigated a significant reduction in healthcare budgets for many Organisation for Economic Cooperation and Development (OECDs) (Health at a Glance 2017, 2017). Extreme pressures have since been forcing action within the pharmaceutical markets, European Union countries have implemented rationale drug use policies. This includes (but is not limited to) mandatory price cuts, promotion of generic multi use medicines and general reductions in access to pharmaceuticals (Carone, Shwierz and Xavier, 2012). These new policies are inciting increased efficiency and cost reduction in the pharmaceutical industry, with the most effective method of this being drug repurposing. Healthcare budgeting can indeed have paradoxical nature, its is critical for modern governments to be efficient and cost effective. Yet there must be sufficient funding to ensure universal access and appropriate quality of healthcare.

Drug repurposing is a method for identifying novel uses for approved or investigational drugs that are not defined in its original indication of use (Ashburn and Thor, 2004). Drug repurposing offers pharmaceutical companies a method of drug production that is both Cost and time efficient. By using pre-known chemical complexes as opposed to new chemical entities there is a great reduction in the risk of failure during clinical trials as (for most repurposed drugs) phase I and II trials have already been completed. Due to the precompleted testing the production time of a repurposed drug is much less than that of a new chemical entity. In most instances of drug repurposing the phase II clinical trials have already been completed, however there is the case of phase III trials. Financial benefits are a result of surpassing the early clinical trials however phase III and phase IV trials will cost the same as a new chemical entity. These culminating factors all cause a significant reduction for the production cost of a repurposed drugs from $2~3 billion to $300 million (Nosengo, 2016). Both of these constraints apply pressure on investors Critically, the most important group that must see benefit are investors in order for pharmaceutical companies to act.

There are two broad spectrums in which repurposed drugs may be discovered; computational and experimental approaches. There are six main methods of computational approaches and two experimental approaches, all of which are being used synergistically in order to improve the output and efficiency of repurposed drugs.

Molecular docking is a computational technique in which binding sites (proteins) are compared with ligands (Drugs) and are screened for complementarity (Kitchen eat al., 2004).

Signature matching is centred on the collation and comparison of signatures unique to each drug. These signatures may compiled from three sets of data, transcription data (RNA), adverse reaction profiles or chemical structures. The first of these three, transcription data, is measured by quantifying gene expression before and also prior to a drug treatment. This molecular signature is then compared with the expression of that gene within a disease-associated model. Providing there is a negative correlation between the disease and the drug model then there may be therapeutic potential for said drug on that phenotype, this process is commonly known as signature reversion principle (SRP). This technique was demonstrated in the repurposing of topiramate, a GABA agonist that was being used at the time to treat epilepsy, for treatment of irritable bowel disease (IBD). Dudley et al. Demonstrated the implications that topiramate may have by using gene expression signatures of IBD (from the National Centre for Biotechnology) and compared that with the expression profile of 164 known drugs (from ConnectivityMap). Their findings implored them to investigate topiramate as a potential treatment, the drug was found to be efficacious for IBD stimulated rat model in which trinitrobenzenesulfonic acid induced the IBD.

Due to the paradigm shift in genomic profiling brought about by the completion of the Human Genome project, vast improvements in genetic profiling technology and greatly reduced costs of genotyping, there has been a significant influx in the number of gene-wide association studies (Pushpakom et al., 2018). These Genome-wide association studies (GWAS) investigate variations in genes that are implicated in common diseases, thereby increasing our knowledge and information available on the disease. Moreover, the information acquired may be used to discover novel drug targets. *

Pathway mapping is related to GWAS, potential targets found by this method may not be acceptable genetic drug targets. If this is the case pathway mapping may be implicated in order to find a more appropriate target either upstream or downstream from the original GWAS discovery. Alternatively there is a method called network mapping, in which networks are constructed based on disease pathology, genetic mapping patterns, the interactions of proteins and/or GWAS data in order to benefit the identification of potential drug candidates.

Retrospective clinical analysis â€“ the systematic analysis of electronic health records, clinical trials and phase IV data may has the potential to be the source of the next quantum jump in drug discovery (Hurle et al., 2013). This form of data mining has the potential to condense and compile vast amounts biotechnological data in order to aid analysis and deductions that can be made regarding possible repurposed drugs (Harpaz, 2012).

Novel data sources

These pressures instigating from increased regulatory intervention, pressure on prices and competition from generics have exacerbated one of the main challenges for 21st century pharmaceutical companies; productivity. These large multinational corporations require on average 2-4 large product releases per year in order to maintain the impressive rate of growth observed pre 1990 (Horrobin, 2001).The implementation of expensive, low yield methods such as high throughput screening and other in vitro methods have produced very little relative to their level of investments and costs. Repurposing previously indicated drugs could potentially be the solution for the plateaued pharmaceutical market. The output of large pharmaceutical companies has stalled with relation to the research and development investment since the early 1990s (please see fig. 1). This decline in output relative to investment

Demographic changes are in addition to economic stresses adding to the pressures for governments providing healthcare. The current expansion of middle class has produced increased demand for healthcare, and an influx in the presence of chronic health conditions. Moreover, increased pressure is being added due to the ageing population. These factors in addition to rising relative prices, expensive developments in medical technology, are predicted to cause a 3.5 to 6 percentage points of GDP by 2050 in the OECD region. Additionally, the suggestion of a non-linear relationship between healthcare expenditure and health outcomes, suggests that there is potential for significant improvements (Joumard, Andre and Nicq, 2010). Chronic conditions such as and cancer are large constituents of budgets

Repurposing Drugs is not only for the benefits of cost and efficiency, but also for the benefit of patients. Currently the majority of widely used cancer treatments could only be considered as barbaric and out dated. Many treatments have poor efficacy, severe side effects and moreover they involve either surgical removal or poisoning the patient (Zhang et al, 2016). This is not in theory the standard of healthcare that should be available given technological advances such as the human genome project. Although there have been large movements towards the idea of personalised medicine, the reality is that this is far from being accomplished for general population cancer patients.

Drug repurposing is not a new concept, rather it is one that is currently undergoing a renewal in popularity. It pertains to the use of known molecules either reformulated, used in conjunction with other molecules or new biotechnology, or administered via a different route. The repurposing of drugs has the potential to produces new efficacious alternatives to current available treatments. This delivers a clinical improvement whilst simultaneously reducing expenditure on costly drug trials and research. Although the repurposing of drugs is widely appreciated in the academic community there is very little relative action being taken by large pharmaceutical companies. Unfortunately, there is little reasoning for this other than the large lack of financial incentive. One particular reasoning for not using repurposed drugs is that for pharmaceutical companies to continue to lead in their field they must continue to entice their market by offering the newest most recent drugs.

Barriers to drug repurposing â€“ There is a significant amount of intellectual property and legal barriers to repurposing old drugs. In the vast majority of pharmaceutical markets it is possible to obtain legal protection of a new repurposed drug, however it must satisfy the prerequisite of newness and innovation. Although this may at first appear easy to obtain many of the known repurposing potentials are already available in literature, meaning that the new formulation will not be considered as innovative, hence any patented must be able to prove that their research and data is different to what is available. Additionally, any research that has been undertaken for that particular indication with that drug, even if failed, has patent protection for 20 years (in the UK). The barriers then to repurposing are much more significant than would be expected, this is certainly one aspect that must change if repurposing is to become more prominent in the pharmaceutical industry. A governing body of pharmaceutical companies must converse with governments and ensure that repurposing is viable with regards to legislation they enforce.

Three elements are crucial to the repurposing efforts, firstly there must be access to clinical trial and safety data for compounds that are being investigated for potential repurposing roles. Secondly the pharmaceutical companies must maximise generation of novel proposals. This is generally best achieved via partnerships with nonprofit organisations

Thalidomide â€“ Initially marketed at a sedative/hypnotic thalidomide was synthesised in 1954 and firstly marketed in West Germany in 1957 under the brand name Contergan. Post release thalidomide was then licensed for use in 46 countries on the European, Asian and African continents (Miller, 1991). Thalidomide was not found to be teratogenic in rodents, higher mammals and humans. It was marketed as an entirely safe, non-side effect sedative/hypnotic (Vargesson, 2015), this marketing continued right up until the drug was banned in 1961.

Thalidomide was never approved in the USA under the instruction of a FDA physician Frances Kelsey, who was later given the Presidentâ€™s Award for Distinguished Federal Civilian Service by John F. Kennedy for heroes role in preventing a thalidomide disaster in the USA (Stephens and Brynner, 2009). The disaster of thalidomide reformed the way in which drugs were tested, additionally this event was a clear demonstration that there is disparity between species in terms of drug reaction/response. Mice especially are much less sensitive to the effects of thalidomide when compared to non-human primates, rabbits etc. (Vargesson, 2015), this then promoted the expansion of drug testing to different species such as non-human primates.

Today thalidomide and its derivatives have a positive reputation despite its extremely negative past, it is currently being marketed as treatment for leprosy, cancers, HIV and Crohnâ€™s Disease. Naturally the prescription and usage of thalidomide are heavily monitored by schemes such as System for Thalidomide Education and Prescribing Safety Program (S.T.E.P.S) (Zeldis et al., 1999). Yet despite its past and the dangers that are commonly associated with the drug there is a new generation of thalidomide sufferers in Brazil, where thalidomide is used to treat leprosy (a common condition there). The impacts are similar to those experienced by children in the UK born to mothers who were prescribed thalidomide (Schuler-Faccini et al., 2007).

Thalidomideâ€™s first indication of potential repurposing was for erythema nodosum leprosum (ENL), an immune mediated complication of leprosy. The condition is characterised by symptoms such as fever arthritis, iritis, neuritis and lymphadenitis, and manifests in the form of multiple erythematous nodules (Polycarpou, Walker and Lockwood, 2017). Thalidomide was approved for treatment of this condition in 1998 (Perri III and Hsu, 2003). Due to the successful treatment of ENL and its anti-angiogenic properties thalidomide has been in a wide range of indications. In 2006 a thalidomide analogue, lenalidomide, was approved for use against newly diagnosed multiple myeloma in addition with dexamethasone (Fda.gov, 2017). It is appropriate for this use due to its inhibitory effect on tumour necrosis factor-Î± (TNF-Î±), which most likely occurs via degradation of TNF-Î± mRNA (Deng, Ding and Granstein, 2003).

In addition to its effect on TNF-Î± thalidomide inhibits NF- Ï°B activation via inhibition of IÏ°B kinase (Mitsiades et al., 2002), this particular protein complex is heavily involved in cell survival, cytokines production, transcription of DNA and therefore the rate of progression of cancer (Hoesel and Schmid, 2013). Thalidomide additionally enhances the production of IL-2 IL-4 and IL-5 which all modulate the immune system to infer anti-cancer activity. Moreover it inhibits IL-6, IL-10 and IL-12, most importantly of this group is IL-6 which is recognised as a very efficacious growth factor for malignant plasma cells. This effect on IL-6 is thought to be one of the main effectors for thalidomide influence on myeloma. Thalidomide will also increase the total number of lymphocytes in addition to CD4+ and CD8+ T cells whilst stimulating production of T lymphocytes (Singhal and Mehta, 2002).

There was a significant breakthrough however in 2010 when thalidomideâ€™s anti-cancer activity was further studied, there was indication that it binds to the protein cereblon. An E3 ubiquitin ligands complex is formed with the proteins, cullin-4A (CUL4A), regulator of Cullins 1 (Roc 1) and damaged DNA binding protein 1 (DDB 1). The complex formed will then tag proteins with ubiquitin therefore tagging them as targets for proteolysis. Thalidomide interjects with the function of this complex which therefore mediates the cytotoxic immune response induced by thalidomide and its analogues. There are two transcription factors that are crucial to thalidomides multiple myeloma cytotoxicity, Ikaros (IKZF1) and Aiolos (IKZF3). Both are selectively bound by cereblon, post binding of thalidomide (or its analogues) cereblonâ€˜s E3 ligase is activated hence causing ubiquitination and degradation of the transcription factors, which results in the reduced expression of interferon regulatory factor 4 (IRF4) and Myc (Stewart, 2014).

Metformin â€“ A study conducted in 2013 concluded that metformin had the highest concentration of any drug in Lake Michigan than any other drug, including caffeine (Blair et al., 2013). Metformin boasts 72 million US prescriptions in 2013, it is a small illustration of how metformin has become the most widely prescribed anti diabetic drug in the world (Agarwal, Jadhav and Deshmukh, 2014). Diabetic patients have increased risk of developing multiple types of cancer, namely breast, pancreatic, bladder, colorectal, bladder and endometrial (Sleire et al., 2017).

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